C Rupérez1, C Lerin2, G Ferrer-Curriu1, M Cairo1, A Mas-Stachurska3, M Sitges3, J Villarroya4, M Giralt1, F Villarroya1, A Planavila5. 1. Departament de Bioquímica i Biomedicina Molecular, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, 08028 Barcelona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Spain. 2. Endocrinology Department, Institut de Recerca Sant Joan de Déu, Barcelona 08950, Spain. 3. Cardiology Department, Thorax Institute, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Spain. 4. Departament de Bioquímica i Biomedicina Molecular, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, 08028 Barcelona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Spain; Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 5. Departament de Bioquímica i Biomedicina Molecular, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, 08028 Barcelona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Spain. Electronic address: aplanavila@ub.edu.
Abstract
OBJECTIVE: High-fat diet-induced obesity leads to the development of hypertrophy and heart failure through poorly understood molecular mechanisms. We have recently shown that fibroblast growth factor-21 (FGF21) is produced by the heart and exerts protective effects that prevent cardiac hypertrophy development and oxidative stress. The aim of this study was to determine the effects of FGF21 on the cardiomyopathy associated with obesity development. RESULTS: Fgf21-/- mice showed an enhanced increase in the heart weight/tibia length (HW/TL) ratio in response to the high-fat diet. In keeping with this, echocardiographic measurements confirmed enhanced cardiac hypertrophy in Fgf21-/- mice. At the cellular level, the area of cardiomyocytes was increased in Fgf21-/- mice fed a high-fat diet. Furthermore, a high-fat diet induced fatty acid oxidation in the hearts of Fgf21-/- mice accompanied by an increase in cardiac oxidative stress. Oil-red O staining revealed the presence of higher amounts of lipid droplets in the hearts of Fgf21-/- mice fed a high-fat diet relative to wt mice fed this same diet. Finally, Fgf21-/- mice fed a high-fat diet showed impaired cardiac autophagy and signs of inactive cardiac lipophagy, suggesting that FGF21 promotes autophagy in cardiomyocytes. CONCLUSIONS: Our data indicate that a lack of FGF21 enhances the susceptibility of mice to the development of obesity-related cardiomyopathy. Furthermore, we demonstrate that this cardiac dysfunction is associated with deleterious lipid accumulation in the heart. An impaired ability of FGF21 to promote autophagy/lipophagy may contribute to lipid accumulation and cardiac derangements.
OBJECTIVE: High-fat diet-induced obesity leads to the development of hypertrophy and heart failure through poorly understood molecular mechanisms. We have recently shown that fibroblast growth factor-21 (FGF21) is produced by the heart and exerts protective effects that prevent cardiac hypertrophy development and oxidative stress. The aim of this study was to determine the effects of FGF21 on the cardiomyopathy associated with obesity development. RESULTS:Fgf21-/- mice showed an enhanced increase in the heart weight/tibia length (HW/TL) ratio in response to the high-fat diet. In keeping with this, echocardiographic measurements confirmed enhanced cardiac hypertrophy in Fgf21-/- mice. At the cellular level, the area of cardiomyocytes was increased in Fgf21-/- mice fed a high-fat diet. Furthermore, a high-fat diet induced fatty acid oxidation in the hearts of Fgf21-/- mice accompanied by an increase in cardiac oxidative stress. Oil-red O staining revealed the presence of higher amounts of lipid droplets in the hearts of Fgf21-/- mice fed a high-fat diet relative to wt mice fed this same diet. Finally, Fgf21-/- mice fed a high-fat diet showed impaired cardiac autophagy and signs of inactive cardiac lipophagy, suggesting that FGF21 promotes autophagy in cardiomyocytes. CONCLUSIONS: Our data indicate that a lack of FGF21 enhances the susceptibility of mice to the development of obesity-related cardiomyopathy. Furthermore, we demonstrate that this cardiac dysfunction is associated with deleterious lipid accumulation in the heart. An impaired ability of FGF21 to promote autophagy/lipophagy may contribute to lipid accumulation and cardiac derangements.
Authors: Kalhara R Menikdiwela; Latha Ramalingam; Fahmida Rasha; Shu Wang; Jannette M Dufour; Nishan S Kalupahana; Karen K S Sunahara; Joilson O Martins; Naima Moustaid-Moussa Journal: Cell Death Dis Date: 2020-02-03 Impact factor: 8.469
Authors: C Ruperez; A Blasco-Roset; D Kular; M Cairo; G Ferrer-Curriu; J Villarroya; M Zamora; F Crispi; F Villarroya; A Planavila Journal: Front Physiol Date: 2022-04-19 Impact factor: 4.755